Silvia Isabel Rech Franke

Iron and genome stability: an update.

Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7mg/day to 18mg/day depending on life stage and gender. Pregnant women need 27mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40-45mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.

A Possible Link Between Iron Deficiency and Gastrointestinal Carcinogenesis

There is definitive evidence that iron overload induces oxidative stress and DNA damage, which can enhance carcinogenic risk. However, other evidence suggests that iron deficiency and anemia also increase oxidative stress and DNA damage, which might increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. The aim of this review is to provide essential background information for the accurate interpretation of future research on iron deficiency and increased GI cancer risk. Based on clinical, epidemiological, and experimental evidence, we discuss how iron deficiency might contribute to increased cancer risk through the impairment of several iron-dependent metabolic functions that are related to genome protection and maintenance (e.g., immune responses against cancer-initiated cells, metabolism of toxic compounds, and redox regulation of DNA biosynthesis and repair). Some epidemiological studies have indicated increased risk of GI tumors among individuals with low iron intake or low somatic iron stores, and in vivo data from rodent cancer models indicates the early progression of GI tumors during iron deficiency. Given the preliminary but consistent evidence relating iron deficiency to cancer risk and the fact that iron deficiency affects about one third of the worlds population, further studies are needed to define the extent to which iron deficiency might increase GI cancer risk.

Uma análise entre índices pressóricos, obesidade e capacidade cardiorrespiratória em escolares

FUNDAMENTO: Durante a infância e adolescencia, o sedentarismo, o excesso de peso e a alimentacao inadequada sao fatores de risco para doencas cronicas, sobretudo obesidade, hipertensao arterial sistemica e diabete melito. A intervencao precoce pode prevenir o desenvolvimento dessas complicacoes. OBJETIVO: Verificar a presenca de fatores de risco cardiovasculares (obesidade e hipertensao arterial) e suas possiveis interacoes com a capacidade cardiorrespiratoria. Metodos: Estudo transversal composto de amostra estratificada por conglomerados, de 1.666 escolares, com idades entre 7 e 17 anos, 873 (52,4%) do sexo masculino e 793 (47,6%) do sexo feminino. Avaliaram-se as pressoes arteriais sistolica (PAS) e diastolica (PAD), indice de massa corporal (IMC), percentual de gordura (%G) e capacidade cardiorrespiratoria. Ainda, PAS e PAD foram correlacionadas com circunferencia da cintura (CC), relacao cintura-quadril (RCQ), somatorio de dobras cutâneas (ΣDC) e capacidade cardiorrespiratoria. RESULTADOS: A avaliacao do IMC dos escolares evidenciou 26,7% de sobrepeso ou obesidade e 35,9% com o percentual de gordura acima de moderadamente alto. Com relacao aos niveis pressoricos, encontraram-se 13,9% e 12,1% de escolares limitrofes e hipertensos, para PAS e PAD, respectivamente. Houve associacao entre hipertensao, obesidade e capacidade cardiorrespiratoria. Observou-se correlacao significativa em relacao a PAS e PAD, para todas as variaveis analisadas, apresentando, ainda, uma relacao fraca a moderada com as variaveis idade, peso, estatura, IMC e circunferencia da cintura. CONCLUSAO: A presenca da hipertensao arterial associada a obesidade e seu reflexo na capacidade cardiorrespiratoria reforcam a importância de se propor, ja na infância, um estilo de vida mais ativo e saudavel.

Relationship between anthropometric measures and cardiovascular risk factors in children and adolescents.

Background Obesity has been identified as an important risk factor in the development of cardiovascular diseases; however, other factors, combined or not with obesity, can influence cardiovascular risk and should be considered in cardiovascular risk stratification in pediatrics. Objective To analyze the association between anthropometry measures and cardiovascular risk factors, to investigate the determinants to changes in blood pressure (BP), and to propose a prediction equation to waist circumference (WC) in children and adolescents. Methods We evaluated 1,950 children and adolescents, aged 7 to 18 years. Visceral fat was assessed by WC and waist hip relationship, BP and body mass index (BMI). In a randomly selected subsample of these volunteers (n = 578), total cholesterol, glucose and triglycerides levels were evaluated. Results WC was positively correlated with BMI (r = 0.85; p < 0.001) and BP (SBP r = 0.45 and DBP = 0.37; p < 0.001). Glycaemia and triglycerides showed a weak correlation with WC (r = 0.110; p = 0.008 e r = 0.201; p < 0.001, respectively). Total cholesterol did not correlate with any of the variables. Age, BMI and WC were significant predictors on the regression models for BP (p < 0.001). We propose a WC prediction equation for children and adolescents: boys: y = 17.243 + 0.316 (height in cm); girls: y = 25.197 + 0.256 (height in cm). Conclusion WC is associated with cardiovascular risk factors and presents itself as a risk factor predictor of hypertension in children and adolescents. The WC prediction equation proposed by us should be tested in future studies.

Iron intake, red cell indicators of iron status, and DNA damage in young subjects

OBJECTIVE This study evaluated the association between primary DNA damage and chromosomal damage with iron intake and red blood cell parameters of iron status in a sample of healthy children and adolescents from a low-socioeconomic community. METHODS The level of primary DNA damage was assessed using an alkaline comet assay and the level of chromosomal damage was assessed using the cytokinesis-block micronucleus assay. A automated complete blood count was used to evaluate red blood cell status. The intake of iron was measured using a food-recall questionnaire. RESULTS According to hemoglobin levels, only 1 of the 30 subjects evaluated was anemic. Nevertheless, 43% of the sampled subjects showed decreased mean corpuscular volume in addition to an increased amount of primary DNA damage (P < 0.05). Mean corpuscular volume was negatively correlated with primary DNA damage (r = -0.429, P = 0.020) but not with chromosomal damage. The association between iron and primary DNA damage showed a U-shaped curve, indicating that an intake of approximately 15 mg of iron per day (up to two-fold of the dietary recommended intake) could minimize primary DNA damage in this age group. The frequency of micronuclei and nucleoplasmic bridges, indicators of chromosomal breakage/loss and chromosomal end-fusions, respectively, showed a negative correlation with iron intake. These results indicate that an intake of iron >15 mg/d could increase genomic stability in binucleated lymphocytes of the same group. CONCLUSION An intake of iron ≥ 15 mg/d can decrease DNA damage in young subjects.

DNA damage and cytotoxicity in adult subjects with prediabetes.

Prediabetes (intermediate hyperglycemia) is a high-risk state for diabetes that is defined by higher than normal glycemic levels that are below the level required for a diagnosis of diabetes. Prediabetes is characterized by oxidative stress, yet the associated DNA damage and cytotoxicity remain unknown to date. Therefore, we evaluated the relationship between glycemic alterations, DNA damage and cytotoxicity in the lymphocytes of individuals with pre-diabetes. Fasting plasma glucose (FPG) and glycated hemoglobin (A1C) levels were quantified and used as inclusion criteria. Anthropometric parameters were also evaluated. The cytokinesis-block micronucleus cytome assay (CBMN Cyt) was used to evaluate DNA damage and cytotoxicity. FPG correlated with A1C (r=0.562, p=0.002). Because A1C is the best predictor of diabetes complications, the association between A1C and the evaluated variables was assessed. The waist-hip ratio correlated with A1C (p<0.01). Regarding DNA damage, the frequency of nucleoplasmic bridges correlated with A1C (p<0.05). Both apoptosis and necrosis correlated with A1C (p<0.05). The overall frequency of DNA damage and cytotoxicity also correlated with A1C (p<0.01). Additional studies evaluating cell cycle and cell death patterns in prediabetes are necessary.

Biological functions of selenium and its potential influence on Parkinson's disease

Parkinsons disease is characterized by the death of dopaminergic neurons, mainly in the substantia nigra, and causes serious locomotor dysfunctions. It is likely that the oxidative damage to cellular biomolecules is among the leading causes of neurodegeneration that occurs in the disease. Selenium is an essential mineral for proper functioning of the brain, and mainly due to its antioxidant activity, it is possible to exert a special role in the prevention and in the nutritional management of Parkinsons disease. Currently, few researchers have investigated the effects of selenium on Parkinson´s disease. However, it is known that very high or very low body levels of selenium can (possibly) contribute to the pathogenesis of Parkinsons disease, because this imbalance results in increased levels of oxidative stress. Therefore, the aim of this work is to review and discuss studies that have addressed these topics and to finally associate the information obtained from them so that these data and associations serve as input to new research.

Orange Juice and Cancer Chemoprevention

Orange juice (OJ) is among the most consumed fruit juices worldwide, and its chemopreventive action is fairly addressed in the literature. This review critically presents the available evidence linking OJ with cancer chemoprevention and on discussing the putative mechanisms and negative health effects. The chemopreventive action of OJ is related to its effect on metabolic enzymes and its antiinflammatory, cytoprotective/apoptotic, hormonal, cell signaling-modulating, antioxidant, and antigenotoxic effects. Most studies on OJ are in vitro, and few are conducted in vivo. Results from in vitro studies must be interpreted carefully because these findings do not consider in vivo bioavailability. However, such results are useful for studying the impact of different processing and storage methods on OJs chemopreventive effect. Evidence of OJs chemoprevention in humans is limited. OJ is antimutagenic in bacteria and antigenotoxic in humans and rodents. Studies using rodent cancer models showed that OJ is cancer chemopreventive, influencing either the induction stage or the promotion stage. The composition and, therefore, the chemopreventive action of OJ might be influenced by different cultivars, climates, extraction methods, packaging, storage temperatures, and shelf lives, among other factors. Epidemiological studies and randomized controlled intervention studies in humans evaluating the chemopreventive effect of OJ, taking into consideration variability in OJ composition, are needed.

Vitamin C Intake Reduces the Cytotoxicity Associated with Hyperglycemia in Prediabetes and Type 2 Diabetes

Hyperglycemia leads to the formation of free radicals and advanced glycation end-products (AGEs). Antioxidants can reduce the level of protein glycation and DNA damage. In this study, we compared the levels of vitamin C intake, which is among the most abundant antioxidants obtained from diet, with the levels of fasting plasma glucose (FPG), glycated hemoglobin (A1C), DNA damage, and cytotoxicity in prediabetic subjects and type 2 diabetic subjects. Our results indicated that there was no significant correlation between FPG or A1C and DNA damage parameters (micronuclei, nucleoplasmic bridges, and nuclear buds). FPG and A1C correlated with necrosis (r = 0.294; P = 0.013 and r = 0.401; P = 0.001, resp.). Vitamin C intake correlated negatively with necrosis and apoptosis (r = −0.246; P = 0.040, and r = −0.276; P = 0.021, resp.). The lack of a correlation between the FPG and A1C and DNA damage could be explained, at least in part, by the elimination of cells with DNA damage by either necrosis or apoptosis (cytotoxicity). Vitamin C appeared to improve cell survival by reducing cytotoxicity. Therefore, the present results indicate the need for clinical studies to evaluate the effect of low-dose vitamin C supplementation in type 2 diabetes.

Recognition memory and DNA damage in undernourished young rats

This study evaluated the recognition memory and the levels of DNA damage (blood and hippocampus) in undernourished young Wistar rats. The experiment was conducted along 14-week with rodents divided in control group (CG, n=8) and undernourished group (UG, n=12) which was submitted to caloric restriction. Nutritional status for undernutrition was defined by Body Mass Index (BMI) ≤0.45g/cm2 and by weighting the organs/tissue (liver, spleen, intestine, peritoneal fat, kidney and encephalon). The Novel Object Recognition Test assessed recognition memory and the Comet Assay evaluated the levels of DNA damage. Student t test, 2-way ANOVA and Pearsons correlation analysis were used and the significance level was of p<0.05. The UG showed lower BMI and organ/tissue weights than CG (p<0.001). In short-term memory, the recognition rate was higher in the UG (p<0.05), only after 4 weeks. In the long-term memory, again recognition rate was higher in the UG than the CG, after 4 weeks (p<0.001) and 14 weeks (p<0.01). The UG showed decreased levels of DNA damage in the blood (p<0.01) and increased levels in the hippocampus (p<0.01). We concluded in this study that the undernutrition by caloric restriction did not cause impairment in recognition memory, however induced DNA damage in the hippocampus.